Cyclic enamides

A representative example is the cyclic enamide 1, containing an optically active A-camphanoyl substituent as a chiral auxiliary82. Treatment of 1 at — 78 C with hydrogen chloride and then a Lewis acid leads to the chiral A -acyliminium intermediate that is alkylated with high stereoselectivity to provide optically active piperidine derivatives. 

The combination of CsF with Si(OMe)4 58 is an efficient catalyst for Michael additions, e.g. of tetralone 130 to methacrylamide, followed hy cyclization of the addition product to the cyclic enamide 131 in 94% yield [67]. Likewise, addition of the lactone 132 to methyl cinnamate affords, after subsequent cyclization with tri-fluoroacetic acid, the lactam 133 in 58% yield [68] whereas < -valerolactam 134, with ethyl acrylate in the presence of Si(OEt)4 59/CsF, gives 135 in 98% yield [69]. Whereas 10mol% of CsF are often sufficient, equivalent amounts of Si(OEt)4 59 seem to be necessary for preparation of 135 [69] (Scheme 3.11). 

Asymmetric hydrogenation of a cyclic enamide (Approach B) had very sparse literature precedents [7]. It should also be noted that preparation of these cyclic imines and enamides is not straightforward. The best method for the synthesis of cyclic imines involves C-acylation of the inexpensive N-vinylpyrrolidin-2-one followed by a relatively harsh treatment with refluxing 6M aqueous HC1, which accomplishes deprotection of the vinyl group, hydrolysis of the amide, and decarboxylation (Scheme 8.6) [8]. 

The double-Heck-approach can also be employed for the preparation of novel heterocyclic compounds as 6/1-25 and 6/1-26 (Scheme 6/1.4) [24]. Thus, the palladium-catalyzed reaction of 6/1-21 and the cyclic enamide 6/1-22 gave a Oil-mixture of 6/1-23 and 6/1-24, which in a second Heck reaction using the palladacene 6/1-15 led to 6/1-25 and 6/1-26 in an overall yield of 44—49%. The synthesis can also be performed as a domino process using a mixture of Pd(OAc)2 and the palladacene 6/1-15. 

Complexes containing one binap ligand per ruthenium (Fig. 3.5) turned out to be remarkably effective for a wide range of chemical processes of industrial importance. During the 1980s, such complexes were shown to be very effective, not only for the asymmetric hydrogenation of dehydroamino adds [42] - which previously was rhodium s domain - but also of allylic alcohols [77], unsaturated acids [78], cyclic enamides [79], and functionalized ketones [80, 81] - domains where rhodium complexes were not as effective. Table 3.2 (entries 3-5) lists impressive TOF values and excellent ee-values for the products of such reactions. The catalysts were rapidly put to use in industry to prepare, for example, the perfume additive citronellol from geraniol (Table 3.2, entry 5) and alkaloids from cyclic enamides. These developments have been reviewed by Noyori and Takaya [82, 83]. 

DuPhos. The exception for rhodium-catalyzed reductions are CnrPhos and BPE-4 [168, 264—268]. MalPhos has proven useful for the reductions of yS-acylamino-acrylates [260]. The ferrocene hybrid (FerroTANE) was referred to earlier (see Section 23.4.1) [167, 222]. The PennPhos ligand is useful for the reductions of cyclic enamides and enol acetates both classes of compounds are difficult for DuPhos itself to reduce with high selectivity [269, 270]. 

Modification of the electronic and steric properties of BINAP, BIPHEMP, and MeO-BI-PHEP led to the development of new efficient atropisomeric ligands. Although most of them are efficient for ruthenium-catalyzed asymmetric hydrogenation [3], Zhang et al. have recently reported an ortho-substituted BIPHEP ligand, o-Ph-HexaMeO-BIPHEP, for the rhodium-catalyzed asymmetric hydrogenation of cyclic enamides (Scheme 1.2) [31]. 

Ene-ynamide 14a gives cyclic enamide 15a, which gives indole derivative 16a by Diels-Alder reaction. In a similar manner, metathesis of ene-ynamide I4b, a one carbon-elongated homolog, followed by Diels-Alder reaction, affords... 

Base-induced isomerization of propargyl amide 29a gives chiral ynamide 30a, which is subjected to ring-closure metathesis to afford cyclic enamide 31a. Diels-Alder reaction of 31a with dimethyl acetylene dicarboxylate (DMAD) gives quinoline derivative 32. In a similar manner, propargyl amide 29b is converted into ynamide 30b, RCM of which gives bicyclic compounds 31b and 31b in a ratio of 1 to 1 (Scheme 10). 

A dissociative first step is anticipated exclusively in photolysis of the endo-cyclic enamide 181 (compare also 80 -a- 85 and 173 -> 174). The reaction is formulated through a ketene intermediate 182. The enamine 183 formed then undergoes hydrolysis to give the oxocarboxylic acid derivative 184 as the product. 

It is reported that the palladium-catalysed intramolecular aromatization of 1,1 -dichloro-9/T-fluoren-9-yIidene (15) may lead to the formation of fullerene fragments.89 The amiulation reaction, under palladium catalysis, between iodoanflines and ketones may yield indole derivatives.90 There have also been studies of the palladium-catalysed carbonylation of o-iodophenols with allenes which may lead to l-benzopyran-4-one derivatives,91 of the intramolecular coupling of phenols with aryl halides,92 and of the intramolecular Heck aiylation of cyclic enamides.93... 

With the same catalyst precursor, attempts to synthesize seven-membered cyclic enamides via ring closing metathesis of N-protected 5-hexenyl enam-ines failed, and selectively led to the formation of six-membered cyclic enamides resulting from initial isomerization of the 5-hexenyl into a 4-hexenyl group followed by cyclization [47]. 

A case is reported164 (Scheme 115) in which a cyclic enamide was reduced at the carbonyl group by LiAlH4 as it was for lactams and amides, leaving untouched the enamine function. 

The same reaction attempted on similar non-cyclic enamides gave no results. The mechanism would involve a transition state in which Mg2 + is simultaneously linked to the NADH model and the substrate, through their respective carbonyl groups. Within this ternary complex an electron migrates from the NADH model to the substrate and this migration is successively followed by a proton transfer from the NADH model radical cation to the radical anion. 

Cyclic enamides 79 are formed by treatment of the 2-arylaminonicotinonitriles 75 with either anhydrous hydrogen chloride in benzene, ethanol or dioxane, or perchloric acid in glacial acetic acid, followed by the acylation of heterocycles 76 by acetic, succinic, trifluoroacetic anhydrides as well as benzoyl chloride67 (equation 28). 

During a search for a route to cyclic enamides, treatment of 246 with 10% Pd/C in tetrahydrofuran at 120°C for 6 hr in a sealed tube was found to... 

It has been reported that RCM of enamides affording five- and six-membered cyclic enamides readily proceeds when the enamides contain a protective group on the N atom. However, an attempt to create a seven-membered cyclic enamide through RCM of 84 resulted in exclusive formation of a six-membered ring 86 (Eq. 12.34) [43]. This reaction was thought to proceed by way of ruthenium-catalyzed isomerization to the intermediary olefin 85, followed by ring closure of the isomerized intermediate to the six-membered enamide 86, which is a typical example of the ring-size effect. 

Ecteinascidin 743 is a potent antitumor agent that was isolated from a marine tunicate. T. Fukuyama et al. applied the intramolecular Heck reaction as the key step in the assembly of the central bicyclo[3.3.1] ring system.Toward this end, the cyclic enamide precursor was exposed to 5 mol% of palladium catalyst and 20 mol% of a phosphine ligand in refluxing acetonitrile to afford the desired tricyclic intermediate in 83% isolated yield. 

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